1526
M. L. Isherwood et al. / Tetrahedron: Asymmetry 23 (2012) 1522–1527
117.1, 116.3, 79.8, 77.8, 52.3, 51.7, 47.3, 41.2, 35.2, 34.1, 31.5, 29.8,
1136, 1098, 867, 801, 723; 1H NMR (CDCl3, 400 MHz): d 8.16–
8.25 (m, 2H), 8.12 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.66
(dd, J = 1.6, 8.8 Hz, 1H), 7.57–7.64 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H),
5.26 (br s, 1H), 4.58–4.80 (m, 1H), 3.60 (s, 3H), 3.22–3.50 (m,
1H), 2.51 (d, J = 16.0 Hz, 1H), 2.15–2.40 (m, 2H), 1.88–1.98 (m,
1H), 1.56–1.68 (m, 1H), 1.35 (s, 9H); 13C NMR (CDCl3, 100 MHz):
d 153.9, 144.4, 138.7, 136.0, 131.71 (q, J = 33.2 Hz), 130.6, 130.5,
129.9, 129.1 (q, J = 3.4 Hz), 124.2 (q, J = 3.6 Hz), 123.2 (CF3, q,
J = 271.3 Hz), 119.7, 118.5, 117.1, 109.8, 79.8, 52.2, 51.4, 36.0,
30.9, 29.6, 29.2, 28.3; HRMS (ESI): (m/z) calcd for C26H28F3N2O4S
[M+H]+: 521.1722, found: 521.1741.
28.4 26.3, 23.3, 21.9, 20.9, 16.2; HRMS (ESI): (m/z) calcd for
C
29H40BrN2O4 [M+H]+: 559.2171, found: 559.2172.
4.2.3. (7S,10R)-tert-Butyl 2-bromo-5,6,7,8,9,10-hexahydro-7,10-
epiminocyclohepta[b]indole-11-carboxylate 2a
To a solution of compound 7a (55.0 g, 98.3 mmol) in tetrahy-
drofuran (600 mL) and MeOH (300 mL) was added LiOHꢂH2O
(12.4 g, 294.8 mmol) dissolved in water (90 mL) at room tempera-
ture. The mixture was stirred vigorously for 2.5 h, quenched with
aqueous saturated NH4Cl solution (500 mL), and extracted with
ethyl acetate (2 ꢁ 750 mL). The combined extracts were dried
(Na2SO4), filtered and concentrated in vacuo. The residue was puri-
fied by column chromatography (SiO2, hexane/ethyl acetate, 7:3)
to afford the pure enantiomer 2a (34.0 g, 92%) as a white solid.
Mp 230–232 °C; enantiomeric purity >99%, Retention time (tr):
16.9 min, HPLC conditions: chiralcel OD, 22 °C, 250 nm, heptane/
4.2.6. (7S,10R)-5-Methyl-2-((3-(trifluoromethyl)phenyl)sulfonyl)-
5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydro-
chloride 1a
To a solution of compound 4a (7.2 g, 13.8 mmol) in tetrahydro-
furan (83.4 mL) was added concentrated HCl (16.6 mL) at 0 °C. The
reaction mixture was slowly allowed to reach room temperature.
After stirring overnight at room temperature the reaction mixture
was quenched with 10% sodium bicarbonate solution (300 mL) and
extracted with CH2Cl2. The CH2Cl2 extract was dried over sodium
sulfate, filtered and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (SiO2, 9:1 dichlorometh-
ane/methanol) to give the free base of compound 1a which was
converted directly to the hydrochloride salt by dissolving it in
dichloromethane and then treating it with 1.25 M HCl in methanol.
The reaction mixture was concentrated in vacuo to afford com-
pound 1a (5.3 g, 84%) as a white solid. Mp 291–293 °C; enantio-
meric purity >99%, retention time (tr): 34.9 min, HPLC conditions:
chiralpak AD, 22 °C, 250 nm, heptane/2-propanol = 80/20, flow
ethanol = 98/2, flow rate = 1.0 mL/min;
½
a 2D0
ꢃ
¼ ꢀ104:4 (c 0.9,
DMSO); IR (KBr): vmax (cmꢀ1) 3343, 2972, 1680, 1463, 1365,
1152, 1101, 978, 811, 682; 1H NMR (DMSO-d6, 400 MHz): d 11.04
(s, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.09 (dd,
J = 2.0, 8.8 Hz, 1H), 5.11 (d, J = 5.2 Hz, 1H), 4.45 (br s, 1H), 3.18–
3.33 (m, 1H), 2.47–2.61 (m, 1H), 2.22 (br s, 1H), 1.99–2.12 (m,
1H), 1.73–1.85 (m, 1H), 1.53–1.65 (m, 1H), 1.35 (s, 5H), 1.27 (s,
4H); 13C NMR (DMSO-d6, 100 MHz): d 152.7, 134.2, 132.5, 126.1,
122.4, 119.1, 114.5, 112.8, 111.6, 78.5, 51.9, 51.0, 35.1, 31.5, 29.1,
28.0; HRMS (ESI): (m/z) calcd for
C
18H22BrN2O2 [M+H]+:
377.0865, found: 377.0877.
4.2.4. (7S,10R)-tert-Butyl 2-bromo-5-methyl-5,6,7,8,9,10-
hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate 3a
To a solution of compound 2a (34.0 g, 90.4 mmol) in DMF
(250 mL) under an argon atmosphere was added NaH (60% disper-
sion in mineral oil) (5.4 g, 135.6 mmol) at 0 °C. The reaction mix-
ture was stirred at room temperature for 1 h before the addition
of iodomethane (7.0 mL, 113.0 mmol). Stirring was continued for
an additional 1 h before the reaction mixture was quenched with
water and extracted with CH2Cl2. The CH2Cl2 extract was washed
with brine, dried over sodium sulfate and concentrated in vacuo
to give 3a (30.0 g, 84%) as a yellow solid. Mp 199–201 °C;
rate = 1.0 mL/min.; ½a D20
¼ þ36:6 (c 0.8, MeOH); IR (KBr): vmax
ꢃ
(cmꢀ1) 2719, 2522, 1598, 1481, 1305, 1139, 1098, 963, 826, 722,
670; 1H NMR (DMSO-d6, 400 MHz): d 9.65 (br s, 2H), 8.48 (d,
J = 1.6 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 8.03 (d,
J = 8.0 Hz, 1H), 7.82–7.89 (m, 1H), 7.75 (dd, J = 2.0, 8.8 Hz, 1H),
7.68 (d, J = 8.8 Hz, 1H), 5.35 (d, J = 5.2 Hz, 1H), 4.41–4.52 (m, 1H),
3.68 (s, 3H), 3.32–3.47 (m, 1H), 3.00 (d, J = 16.8 Hz, 1H), 2.22–
2.39 (m, 2H), 2.12–2.03 (m, 1H), 1.73–1.83 (m, 1H); 13C NMR
(DMSO-d6, 100 MHz): d 143.9, 138.7, 134.9, 131.2, 131.1, 130.4,
130.0 (q, J = 32.5 Hz), 129.8 (q, J = 3.4 Hz), 123.2 (CF3, q,
J = 271.3 Hz), 123.1 (q, J = 5.5 Hz), 119.8, 119.0, 111.1, 111.0, 52.6,
51.8, 34.3, 29.8, 29.6, 26.8; Purity (HPLC): 99.2% (tR = 21.5 min);
HRMS (ESI): (m/z) calcd for C21H20F3N2O2S [M+H]+: 421.1198,
found: 421.1200.
½
a 2D0
ꢃ
¼ þ121:8 (c 1.1, CHCl3); IR (KBr): vmax (cmꢀ1) 2968, 2927,
1688, 1470, 1389, 1163, 1096, 975, 865, 792; 1H NMR (CDCl3,
300 MHz): d 7.61 (d, J = 1.5 Hz, 1H), 7.20 (dd, J = 1.5, 8.7 Hz, 1H),
7.09 (d, J = 8.7 Hz, 1H), 5.15 (br s, 1H), 4.68 (br s, 1H), 3.55 (s,
3H), 3.23–3.49 (m, 1H), 2.47 (d, J = 16.2 Hz, 1H), 2.08–2.37 (m,
2H), 1.85–1.97 (m, 1H), 1.53–1.68 (m, 1H), 1.38 (s, 9H); 13C NMR
(CDCl3, 75 MHz): d 153.9, 135.3, 133.9, 125.9, 123.2, 119.8, 114.9,
112.4, 110.2, 79.5, 52.3, 51.4, 36.0, 30.8, 29.3, 29.2, 28.4; HRMS
(ESI): (m/z) calcd for C19H24BrN2O2 [M+H]+: 391.1021, found:
391.1021.
4.3. Experimental procedures for the preparation of 1b
4.3.1. (7R,10S)-11-tert-Butyl 5-((1S,2R,5S)-2-isopropyl-5-meth-
ylcyclohexyl) 2-bromo-7,8,9,10-tetrahydro-7,10-epiminocyclohep-
ta[b]indole-5,11(6H)-dicarboxylate 7b
Compound 7b was prepared from 2 (15.0 g, 39.8 mmol) and
(1S)-(+)-menthyl chloroformate, according to the procedure de-
scribed for the synthesis of 7a. Light yellow solid, Yield 9.5 g,
4.2.5. (7S,10R)-tert-Butyl 5-methyl-2-((3-(trifluoromethyl)phenyl)-
sulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-
11-carboxylate 4a
85%; Mp 185–187 °C; ½a D20
¼ þ105:0 (c 1.2, CHCl3); IR (KBr): vmax
ꢃ
A mixture of compound 3a (10.0 g, 25.5 mmol), sodium 3-(tri-
fluoromethyl)benzenesulfinate (7.4 g, 31.9 mmol), di-palladium-
tris(dibenzylideneacetone) (1.17 g, 1.27 mmol), cesium carbonate
(12.5 g, 38.3 mmol), and xantphos (1.4 g, 2.5 mmol), was taken
up in anhydrous toluene (150.0 mL). The reaction flask was purged
with argon and refluxed at 120 °C for 4 h. After cooling to ambient
temperature, the reaction mixture was diluted with ethyl acetate
(250 mL) and filtered through a Celite bed. The filtrate was concen-
trated in vacuo and the residue purified by flash column chroma-
tography (SiO2, 7:3 hexane/ethyl acetate) to afford compound 4a
(cmꢀ1) 2950, 2868, 1732, 1693, 1458, 1387, 1164, 1125, 982,
866, 801, 758; 1H NMR (CDCl3, 400 MHz): d 8.02 (d, J = 8.4 Hz,
1H), 7.57 (d, J = 1.6 Hz, 1H), 7.35 (dd, J = 1.6, 8.8 Hz, 1H), 5.12 (br
s, 1H), 4.92 (dt, J = 4.4, 10.8 Hz, 1H), 4.44–4.77 (m, 1H), 3.42–3.62
(m, 1H), 2.81 (d, J = 17.6 Hz, 1H), 2.09–2.37 (m, 3H), 1.90–2.02
(m, 2H), 1.51–1.82 (m, 5H), 1.42 (s, 9H), 1.07–1.22 (m, 2H), 0.89–
1.01 (m, 1H), 0.94 (t, J = 6.4 Hz, 6H), 0.80 (d, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz): d 153.7, 151.1, 134.5, 133.6, 128.6, 126.5,
121.6, 120.1, 117.1, 116.2, 79.8, 77.8, 52.3, 51.7, 47.3, 41.2, 35.1,
34.1, 31.5, 29.8, 28.4 26.3, 23.3, 21.9, 20.9, 16.2; HRMS (ESI): (m/
z) calcd for C29H40BrN2O4 [M+H]+: 559.2171, found: 559.2180.
(7.3 g, 55%) as a light-yellow solid. Mp 189–191 °C; ½a D20
¼ ꢀ64:6
ꢃ
(c 1.3, CHCl3); IR (KBr): vmax (cm-1) 2975, 1681, 1406, 1322,